Therapeutics, Pharmacology and Clinical Toxicology Vol XIV, Number 3 September 2010 Pages 176-182 © Copyright reserved 2010
REWIEW
CURRENT STRATEGIES AND CONCEPTS FOR PREVENTING INFECTIONS AFTER SOLID ORGAN TRANSPLANTATION
M. Oltean The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
Abstract. The posttransplant immunosuppressive medication renders transplant recipients susceptible to bacterial, viral or fungal infections. A significant proportion of these infectious complications can be successfully prevented through careful donor and recipient screening, pretransplant infection control and immunizations. Moreover, an array of measures in the posttransplant period such as antiviral prophylaxis as well as simple yet meaningful changes in the lifestyle can further contribute to decreasing the frequency of infections. This not exhaustive review outlines these main measures and highlights the current prevention strategies, based on the available data, consensus and protocols. Keywords: infection control, prophylaxis, transplantation, lifestyle
Introduction
O
rgan transplantation recorded a tremendous development over the last decade, both regarding the number of patients being transplanted and in terms of results. According to the statistics of the Swedish Society of Transplantation, 464 organs were transplanted in Sweden during 1999 while the figure rose with over 40% reaching 666 organs transplanted in 2009 [1]. Moreover, despite a poorer quality of the organs procured and broadening the eligibility criteria for acceptance on the waiting list, five-year graft survival approaches 80% and 70% following kidney and liver transplantation respectively [2,3,4]. Undoubtedly, the major reasons behind this success are the refinements in both the induction and maintenance immunosuppression [5,6,7]. However, the contribution of other
Mihai Oltean The Transplant Institute, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden e-mail:
[email protected] 176
factors such as the improved pre- and posttransplant management, patient selection, infectious prophylaxis and treatment, avoiding disease recurrence as well as the prevention of fatal cardiovascular events should not be overlooked [8,9,10]. The present overview will summarize the current specific and general measures aimed at reducing the infectious complications after transplantation.
The timing of infections after transplantation The timetable of the posttransplant infections put together by Fishman and Rubin more than a decade ago maintains its validity [11]. According to it, the spectrum of the infections occurring early (first month) after transplantation is quite similar with those occurring in non-immunosuppressed surgical patients and includes the same nosocomial bacterial or fungal infections of the surgical wound, lungs, urinary tract or vascular access devices. Important factors in determining the incidence of such infections are the preoperative patient status but also technical details and the difficulty of the surgical procedure. These may result in forTherapeutics, Pharmacology and Clinical Toxicology
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eign bodies, devitalized tissue or may be followed by the prolonged presence of drains, protracted intubation or unjustifiably long maintenance of the urinary catheters or stents [12]. Transfusion of large volumes of blood products, longer cold ischemia time, the use of a choledochojejunostomy (Roux-en-Y) instead of a choledochostomy, (ductto-duct) for the biliary anastomosis, the increased risk for intraabdominal fluid collections, bile leaks and repeated abdominal surgery put the liver transplant patients at increased risk for developing early infections [13,14,15,16]. Antimicrobial prophylaxis can only delay the occurrence of infection in such circumstances unless the technical or anatomical problems are timely addressed, in association with correct antimicrobial therapy. Under this period patients may become infected with nosocomial, antimicrobial-resistant bacteria, including methicillin-resistant Staphylococcus aureus, vancomycinresistant Enterococcus faecalis, Clostridium difficile, and antimicrobial resistant gram-negative bacteria. During the intermediate period (the first six months), the nature of infections changes and patients are mostly at risk for developing several types of opportunistic infections (Pneumocystis, Aspergillus, Leishmania, Nocardia) due to the cumulative effect of the immunosuppression although some problems from the early postoperative period can still persist. During this period the immunomodulating viruses (particularly CMV, but also EBV, other human herpesviruses, HBV and HCV) start to exert clinically significant effects [17]. Together with allograft rejection, these viruses are responsible for the majority of febrile episodes that occur over the first half year after transplantation [18]. The opportunistic infections are rare during the first six months in patients receiving stable and reduced maintenance doses of immunosuppression and having an adequate graft function. Beyond the first half year after transplantation the spectrum of the infections changes and depends largely on the result of the transplantation. Patients with well-functioning grafts, uncomplicated course and receiving minimal maintenance therapy may present the common, community-acquired bacterial infections seen in the general population (mostly respiratory). On the other extreme, patients that previously had acute rejection episodes, viral infections or incipient chronic rejection may experience uncommon opportunistic infections such as listeriosis, nocardiosis, cryptococcosis and aspergillosis, mostly due to the more intense immunosuppressive regimen. XIV, Vol.14, Number 3/2010
Pretransplant screening and management The great majority of the patients have a long history of hospitalizations and may be colonized with health-care associated microorganisms. All active infections should be eradicated before transplantation. Kidney transplant candidates may have infection foci due to the peritoneal dialysis catheters or related to the hemodialysis access. Liver transplant candidates are susceptible to spontaneous bacterial peritonitis and aspiration pneumonia while lung transplant candidates, particularly those with cystic fibrosis, are subject to pneumonias, sometimes with multiresistant strains. Respiratory colonization with Aspergillus is not generally considered to be a contraindication to transplantation per se but should trigger a careful search for an active disease, that should be completely treated before listing the patient for lung transplantation [19]. Bacteremia and candidemia before transplantation are of particular importance for any organ transplant and must be fully and effectively treated to avoid not only early posttransplant sepsis bursts but also the formation of mycotic aneurysms at the anastomotic suture lines, that may rupture and often lead to patient death [20,21]. We put a particular emphasis on oral health. All nonrestorable teeth should be extracted and any active infection, such as purulent periodontal infections or abscessed teeth should be eliminated while antibiotics should be given to the patient before and after the dental treatment to prevent systemic infection. In liver transplant candidates, which are more prone to bleeding, one should consider careful suction and hemostasis during oral surgery since swallowing blood may increase the risk for hepatic coma in patients with end stage liver disease. A key step in preventing posttransplant infections is the routine serological testing of the organ donor to detect such as CMV, HBV, HCV, HIV and syphilis that may transmit the infection into the recipient [19,22]. Eventual positive finds, particularly CMV infection, do not exclude these organs from being transplanted into selected recipients [23,24] (detailing the allocation of such infected organs is however beyond the purpose of this review). Serology for CMV is important for organ allocation but also for identifying the high risk patients and choosing the right antiviral prophylaxis regimen. The advent of effective antiviral drugs has somehow reduced the importance of CMV matching [24]. However, knowing the CMV status in both donor and recipient and choosing an adequate prophylaxis 177
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or preemptive regimen is particularly important not only in preventing the CMV disease. Besides greatly lowering the rate of CMV disease, antiviral prophylaxis may decrease the frequency of allograft rejection, since the relation between rejection and CMV appears to be bidirectional (CMV may cause rejection while the inflammation caused by rejection and some antirejection therapies increase viral replication). In addition, the choice of a customized regimen would allow that low risk patients would not receive CMV prophylaxis more than six months, thus minimizing the nephrotoxic effects of the current antivirals (gancyclovir, valgancyclovir) [25]. The screening for the hepatitis viruses is important to avoid transmission of the disease into non-infected individuals but also for organ allocation. For instance, the actual regulations in the Scandinavian transplant cooperation (Scandiatransplant) prohibit the use of livers from HBV surface antigen positive donors while other organs may be used for HBsAg+ recipients. According to the same rules, livers from HBV core antibody positive donors can be used for emergency situations at the decision of the surgeon while other organs may be used for HBsAg+ recipients [26,27]. If the donor is also HBsAb+, or if specific Ig (single dose prior to revascularization) is given to the recipient, organs (except for the liver) can be used in any recipient. Knowing both donor and recipient HCV status is essential since HCV is transmitted almost always after the transplantation of organs from anti–HBC-positive donors to HBCnegative recipients [28,29]. HCV infection usually takes a chronic and slowly progressive course with cirrhosis and liver cancer developing faster than in non-transplanted individuals [17,30]. However, organs other than the liver from HCV infected donors (heart, kidney, lungs) can be offered to HCV-RNA positive recipients after thoroughly informed consent [31,32,33]. Since the genotype combination is important for the rate of re-infection, genotyping of HCV patients should be performed before the acceptance on the waiting list. The recipient status for other viruses such as EBV, VZV or HTLV that may cause serious posttransplant conditions (posttransplant lymphoproliferative disease, primary varicella infection, T-cell leukemia) may also be relevant, increase the posttransplant awareness and allow for early interventions such as lowering the immunosuppression or immunizations (see below). Tuberculosis may cause significant morbidity and even death after transplantation, particularly in 178
endemic areas [34,35]. Moreover, diabetes mellitus and chronic liver disease increase the risk for posttransplant tuberculosis [36]. Treating tuberculosis after transplantation may be particularly difficult due to the interactions of antituberculous medications (mainly rifampicin) with the calcineurin inhibitors and rapamycin. Therefore, an intense search for the active tuberculosis focus should be conducted in the transplant candidates with a positive PPD test result before transplantation. The patient should be inactivated (redrawn from the waiting list) and any eventual active disease should be fully treated before re-listing for transplantation. Antiviral prophylaxis As briefly discussed earlier, CMV infection is important not only because of the risk for tissue invasive disease but also due to its relationship with acute rejection. CMV used to be a significant morbidity and mortality cause in the past but the advent of effective oral antiviral agents revolutionized the prevention of post-transplantation cytomegalovirus disease (and other herpesvirus infections) [37]. To date, two different preventive strategies are used. One approach implies that all at-risk patients will receive the antiviral usually for 3-6 months (the universal prophylaxis). The other strategy aims at detecting infection before symptoms arise and is based on intensified monitoring of the CMV load or antigenemia at predefined intervals, followed by initiating the antiviral therapy and lowering the immunosuppression whenever the assays become positive (the preemptive therapy) [38]. Both these strategies have advantages and drawbacks. Besides preventing other viral infections such as herpes simplex virus, varicella–zoster virus, EBV, and human herpesvirus 6 universal antiviral prophylaxis appears also to reduce the risk of other infections such as pneumocystis, candida and bacterial infections [39,40,41]. The preemptive strategy is cheaper because less antiviral therapy is administered and the monitoring is not as expensive as the cost of the drug. In addition, the preemptive strategy exposes fewer patients to the toxic effects of the drug therapy but requires extra costs and coordination for monitoring and outpatient care. The routine use of antiviral prophylaxis (but also changes in the immunosuppressive therapy) has however lead to changes in the epidemiology of CMV disease and the occurrence of delayed-onset primary CMV disease [42]. The treatment may Therapeutics, Pharmacology and Clinical Toxicology
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induce significant nephrotoxicity and carries the risk for bone marrow depression [42]. Gancyclovir resistance has also been reported [43]. Vaccinations Every effort should be made to update the immunizations in the adult patient before transplantation, as the posttransplant immunosuppression may prevent the development of an efficient immunologic response. Both hemodialysis and kidney transplant patients may need to undergo revaccination more frequently (e.g., every 2–3 years) than healthy individuals [44,45]. Live vaccines should be avoided in the last two months before transplantation. Consequently, since the transplant date cannot be safely anticipated, these vaccines should be considered early after listing for transplantation. Particular attention should be given to the varicella vaccine to varicella-naive children listed for transplantation. Several other live attenuated vaccines such as the Bacille Calmette Guerin, measles or measles-mumps-rubella (MMR) should follow the same precautions [46]. Pneumococcal pneumonia and sepsis are important causes of morbidity in transplant recipients, even if a longer time elapsed after transplantation. Some patients with end-stage kidney disease develop lower titers in response to the vaccine because of uremia or other underlying diseases [47], emphasizing the need for periodic revaccination in case of long time spent on the waiting list. Moreover, many patients may undergo functional or surgical splenectomy, either prior or during the transplantation. According to the current recommendations, vaccination with the pneumococcal polysaccharide should be undertaken before transplantation. Vaccination of some immunosuppressed individuals with H.influenzae type B (HIB) conjugate vaccines may result in lower titers than in healthy recipients [5]. Many adult patients have already developed protective titers, if they are not asplenic. However, it is indicated to complete the HIB primary vaccination series in children listed for transplantation. Tetanus-diphtheria toxoid. Tetanus-diphtheria toxoid (Td) boosters appear to be generally well tolerated after transplantation and many centers proceed to such an immunization after transplantation. Annual influenza vaccination is recommended, although a controversy persists whether it may increase the risk of rejection [48,49]. The benefits of vaccination seem however to surpass the risks, so that during the 2009 -2010 H1N1 pandemic all XIV, Vol.14, Number 3/2010
transplanted patients at the Sahlgrenska Transplant Institute underwent vaccination. It is generally acknowledged that hepatitis B virus infection may be more severe, and is more likely to progress towards chronic disease in transplanted patients. The recombinant HBV vaccines (Engerix-B, Recombivax HB) are less immunogenic in transplant candidates. However, despite a lower response in patients with kidney and liver end-stage disease (40%–75%) compared with the general population (96%), this situation is still better than the response obtained after transplantation [50,51,52,53]. Hepatitis vaccination is even more important in countries with high prevalence of HBV. Such a strategy may allow transplantation of organs (other than the liver) from a donor who is hepatitis B surface antigen negative and core antibody positive into selected groups of recipients. Vaccination for hepatitis B has been specifically recommended before liver transplantation to prevent de novo graft infection as well as in renal transplant recipients because of the increased risk of exposure [54]. Adapting the environment and the lifestyle inand outside the hospital The importance of epidemiologic exposure is often neglected when a longer time has lapsed after transplantation. Epidemiologic exposure occurs in the community and the hospital and while awareness towards it is higher in the early posttransplant period, this tends to decrease after a while. The staff should wash their hands before and after each patient interaction to prevent the spread of nosocomial pathogens. Care should be taken when moving contaminated medical equipment between patients and patient rooms or when the patient is exposed to contaminated air during travel to or from clinical procedures such as surgery or radiologic imaging. Thus, transplant recipients should be equipped with special masks when transported through high-risk areas (elevators, construction areas, halls) within the hospital [55]. Plants and flowers are potentially contaminated with gram-negative organisms and should not be allowed in patient rooms. Care must be taken to ensure that patients are not exposed to Legionella, from showers, toilet facilities, and contaminated air-conditioning systems, or to Aspergillus spores, from construction sites. Showers, toilets, and air-conditioning systems should be monitored and HEPA-filtered air-handling systems should be used when the air supply is potentially contaminated [56,57]. Simpler but rather effective alternatives are for instance leaving the tap water 179
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or the showers running for several minutes before use and repeatedly cleaning the floors [58]. Both patients and family members should be instructed during their initial hospitalization (ideally before transplantation) and get familiar with the routines that may reduce the incidence of infectious complications after hospital discharge. The precautions should continue after discharge. Transplant recipients not immunized to varicellazoster virus should avoid exposure to persons having chicken pox or shingles and anyone with a localized rash after vaccination. If a contact nevertheless occurs, recipients should immediately contact a physician to receive varicella-zoster immunoglobulin. Transplanted individuals should avoid contact with children and adults having any active respiratory virus infections or another transmissible disease. Avoiding exposure to infections should not be chosen on the expense of social isolation, which may have adverse psychological and developmental effects, particularly in children. A Finnish study indicated that resuming the attendance of day care three months after transplantation is not hazardous to the transplant recipients [59]. Fruits and vegetables should be thoroughly washed. Transplant recipients should avoid unpasteurized fruit juices and milk as well as dairy products made with unpasteurized milk. All meat, eggs, and seafood should be thoroughly cooked to decrease exposure to Salmonella species, Campylobacter jejuni, Listeria monocytogenes, Escherichia coli, and hepatitis A virus. If the safety of drinking water is questionable, the water should be boiled for 1 full minute before it is used. The tap water should be left running several minutes before drinking it and showers should be preferred to bath for personal hygiene. Gardening and cleaning up after pets should be minimized or done wearing gloves. Changing cat litter boxes daily will eliminate the risk of toxoplasmosis because the oocysts do not have time to sporulate. Travels in areas requiring vaccinations or malaria prophylaxis should be discussed with the transplant physician a reasonable length of time before departure to allow for the installation of immunity.
transplantation. A broad range of measures both in the pre- and posttransplant period may decrease the rate and severity of infectious complications and should be familiar to all categories of medical personnel involved in the care of such patients.
Conclusions
15. Nemes B, Sarvary E, Sotonyi P, et al. Factors in association with sepsis after liver transplantation: the Hungarian experience. Transplant Proc 2005; 37 (5): 2227.
Reducing the frequency of infectious complications after transplantation through preventive measures may avoid life-threatening infections, reduce the potentially adverse effects of the antibiotics and ultimately improve the outcome after 180
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